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1.
Angew Chem Int Ed Engl ; 62(5): e202212190, 2023 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-36281761

RESUMO

We describe the total synthesis of the macrodiolide C(13)/C(13')-bis(desmethyl)disorazole Z through double inter-/intramolecular Stille cross-coupling of a monomeric vinyl stannane/vinyl iodide precursor to form the macrocycle. The key step in the synthesis of this precursor was a stereoselective aldol reaction of a formal Evans acetate aldol product with crotonaldehyde. As demonstrated by X-ray crystallography, the binding mode of C(13)/C(13')-bis(desmethyl)disorazole Z to tubulin is virtually identical with that of the natural product disorazole Z. Likewise, C(13)/C(13')-bis(desmethyl)disorazole Z inhibits tubulin assembly with at least the same potency as disorazole Z and it appears to be a more potent cell growth inhibitor.


Assuntos
Macrolídeos , Tubulina (Proteína) , Aldeídos , Estereoisomerismo
2.
Proc Natl Acad Sci U S A ; 116(9): 3774-3783, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808763

RESUMO

Establishing causal links between bacterial metabolites and human intestinal disease is a significant challenge. This study reveals the molecular basis of antibiotic-associated hemorrhagic colitis (AAHC) caused by intestinal resident Klebsiella oxytoca Colitogenic strains produce the nonribosomal peptides tilivalline and tilimycin. Here, we verify that these enterotoxins are present in the human intestine during active colitis and determine their concentrations in a murine disease model. Although both toxins share a pyrrolobenzodiazepine structure, they have distinct molecular targets. Tilimycin acts as a genotoxin. Its interaction with DNA activates damage repair mechanisms in cultured cells and causes DNA strand breakage and an increased lesion burden in cecal enterocytes of colonized mice. In contrast, tilivalline binds tubulin and stabilizes microtubules leading to mitotic arrest. To our knowledge, this activity is unique for microbiota-derived metabolites of the human intestine. The capacity of both toxins to induce apoptosis in intestinal epithelial cells-a hallmark feature of AAHC-by independent modes of action, strengthens our proposal that these metabolites act collectively in the pathogenicity of colitis.


Assuntos
Enterocolite Pseudomembranosa/genética , Enterotoxinas/metabolismo , Interações entre Hospedeiro e Microrganismos/genética , Klebsiella oxytoca/genética , Animais , Benzodiazepinonas/metabolismo , Benzodiazepinonas/toxicidade , Dano ao DNA/efeitos dos fármacos , Enterocolite Pseudomembranosa/microbiologia , Enterocolite Pseudomembranosa/patologia , Enterotoxinas/biossíntese , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Humanos , Intestinos/microbiologia , Intestinos/patologia , Infecções por Klebsiella/genética , Infecções por Klebsiella/microbiologia , Klebsiella oxytoca/metabolismo , Klebsiella oxytoca/patogenicidade , Camundongos , Microtúbulos/efeitos dos fármacos , Oxiquinolina/análogos & derivados , Oxiquinolina/metabolismo , Oxiquinolina/toxicidade , Peptídeos/metabolismo , Peptídeos/toxicidade
3.
Int J Mol Sci ; 23(7)2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-35408808

RESUMO

Microtubule targeting agents (MTAs) have been exploited mainly as anti-cancer drugs because of their impact on cellular division and angiogenesis. Additionally, microtubules (MTs) are key structures for intracellular transport, which is frequently hijacked during viral infection. We have analyzed the antiviral activity of clinically used MTAs in the infection of DNA and RNA viruses, including SARS-CoV-2, to find that MT destabilizer agents show a higher impact than stabilizers in the viral infections tested, and FDA-approved anti-helminthic benzimidazoles were among the most active compounds. In order to understand the reasons for the observed antiviral activity, we studied the impact of these compounds in motor proteins-mediated intracellular transport. To do so, we used labeled peptide tools, finding that clinically available MTAs impaired the movement linked to MT motors in living cells. However, their effect on viral infection lacked a clear correlation to their effect in motor-mediated transport, denoting the complex use of the cytoskeleton by viruses. Finally, we further delved into the molecular mechanism of action of Mebendazole by combining biochemical and structural studies to obtain crystallographic high-resolution information of the Mebendazole-tubulin complex, which provided insights into the mechanisms of differential toxicity between helminths and mammalians.


Assuntos
Tratamento Farmacológico da COVID-19 , Mebendazol , Animais , Antivirais/farmacologia , Mamíferos , Mebendazol/farmacologia , Microtúbulos , SARS-CoV-2 , Tubulina (Proteína)
4.
Chemistry ; 27(19): 5936-5943, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33078440

RESUMO

We describe the convergent synthesis of three prototypical examples of a new class of analogues of the complex, cytotoxic marine macrolide (-)-zampanolide that incorporate an embedded N-substituted morpholine moiety in place of the natural tetrahydropyran ring. The final construction of the macrolactone core was based on a high-yielding intramolecular HWE olefination, while the hemiaminal-linked side chain was elaborated through a stereoselective, BINAL-H-mediated addition of (Z,E)-sorbamide to a macrocyclic aldehyde precursor. The synthesis of the common functionalized morpholine building block involved two consecutive epoxide openings with tosylamide and the product of the first opening reaction, respectively, as nucleophiles. Of the three morpholino-zampanolides investigated, the N-acetyl and the N-benzoyl derivatives both exhibited nanomolar antiproliferative activity, thus being essentially equipotent with the natural product. In contrast, the activity of the N-tosyl derivative was significantly reduced.


Assuntos
Antineoplásicos , Produtos Biológicos , Produtos Biológicos/farmacologia , Macrolídeos/farmacologia , Estrutura Molecular , Morfolinas/farmacologia , Estereoisomerismo
5.
Scand J Med Sci Sports ; 31(6): 1268-1275, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33559944

RESUMO

The purposes of this study were to determine the impact of 6 weeks of whole-body vibration training (WBVT) on maximum voluntary plantar flexor strength, muscle activity via surface electromyography (EMG), and muscle architecture measured at rest and during maximal contraction at different ankle joint angles in young healthy adults. Using a single-blind study design, 28 healthy men and women were randomly assigned to control (CG; N = 14, 7 women) or whole-body vibration training (WBVG; N = 14, 7 women) groups. Vibration training (20-25 minutes; standing with knees flexed) was performed 3 week-1 for 6 weeks (18 sessions). Maximum isometric plantar flexor torque, muscle activity (medial and lateral gastrocnemius EMG) and medial gastrocnemius fascicle angle and length at rest and maximum contraction were tested at four ankle joint angles (ranging 45° to -15°; 0° = anatomical) before and after training. Significant increases (24.7%-37.5%) were observed in peak torque (N∙m∙kg-1 ;%) at -15°, 0°, 15° and 30° joint angles from pre- to post-intervention in WBVG, which were different to CG (no change) and greater at longer muscle lengths. No between-group differences were observed in changes in EMG amplitudes measured during contraction or muscle architecture parameters at rest or during contraction. Six weeks of WBVT in young, healthy adults increased isometric plantarflexion strength at multiple joint angles, without detectible changes in EMG, muscle architecture, or body composition. Therefore, WBVT can significantly improve maximum plantar flexor strength at multiple joint angles (muscle lengths) in young healthy men, although the mechanisms underpinning the changes are currently unclear.


Assuntos
Contração Isométrica/fisiologia , Perna (Membro) , Músculo Esquelético/fisiologia , Vibração , Adulto , Eletromiografia , Feminino , Humanos , Masculino , Força Muscular/fisiologia , Músculo Esquelético/anatomia & histologia , Descanso , Método Simples-Cego , Fatores de Tempo , Torque , Adulto Jovem
6.
Cancer Cell Int ; 20: 170, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32467666

RESUMO

BACKGROUND: Drug resistance and chemotherapy-induced peripheral neuropathy continue to be significant problems in the successful treatment of acute lymphoblastic leukemia (ALL). 5,7-Dibromo-N-alkylisatins, a class of potent microtubule destabilizers, are a promising alternative to traditionally used antimitotics with previous demonstrated efficacy against solid tumours in vivo and ability to overcome P-glycoprotein (P-gp) mediated drug resistance in lymphoma and sarcoma cell lines in vitro. In this study, three di-brominated N-alkylisatins were assessed for their ability to retain potency in vincristine (VCR) and 2-methoxyestradiol (2ME2) resistant ALL cell lines. For the first time, in vitro neurotoxicity was also investigated in order to establish their suitability as candidate drugs for future use in ALL treatment. METHODS: Vincristine resistant (CEM-VCR R) and 2-methoxyestradiol resistant (CEM/2ME2-28.8R) ALL cell lines were used to investigate the ability of N-alkylisatins to overcome chemoresistance. Interaction of N-alkylisatins with tubulin at the the colchicine-binding site was studied by competitive assay using the fluorescent colchicine analogue MTC. Human neuroblastoma SH-SY5Y cells differentiated into a morphological and functional dopaminergic-like neurotransmitter phenotype were used for neurotoxicity and neurofunctional assays. Two-way ANOVA followed by a Tukey's post hoc test or a two-tailed paired t test was used to determine statistical significance. RESULTS: CEM-VCR R and CEM/2ME2-28.8R cells displayed resistance indices of > 100 to VCR and 2-ME2, respectively. CEM-VCR R cells additionally displayed a multi-drug resistant phenotype with significant cross resistance to vinblastine, 2ME2, colchicine and paclitaxel consistent with P-gp overexpression. Despite differences in resistance mechanisms observed between the two cell lines, the N-alkylisatins displayed bioequivalent dose-dependent cytotoxicity to that of the parental control cell line. The N-alkylisatins proved to be significantly less neurotoxic towards differentiated SH-SY5Y cells than VCR and vinblastine, evidenced by increased neurite length and number of neurite branch points. Neuronal cells treated with 5,7-dibromo-N-(p-hydroxymethylbenzyl)isatin showed significantly higher voltage-gated sodium channel function than those treated with Vinca alkaloids, strongly supportive of continued action potential firing. CONCLUSIONS: The N-alkylisatins are able to retain cytotoxicity towards ALL cell lines with functionally distinct drug resistance mechanisms and show potential for reduced neurotoxicity. As such they pose as promising candidates for future implementation into anticancer regimes for ALL. Further in vivo studies are therefore warranted.

7.
Arch Pharm (Weinheim) ; 349(9): 749-61, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27404773

RESUMO

A series of new sulfanyltriazolylnaphthalenols (10a-f and 13a-f) and sulfanyltriazolylnaphthalene-1,4-diones (14a-f) were synthesized and evaluated against a panel of cancer cell lines. Among the tested compounds, 10b and 10d showed the best anti-proliferative activity with GI50 values ranging from 2.72 to 10 and 3.13 to 13.1 µM, respectively, in several of the tumor cell lines tested. Compound 10d is highly selective toward leukemia cell lines and can be regarded as a good model for the development of new anti-leukemic agents.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Naftalenos/síntese química , Naftalenos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Naftalenos/química , Relação Estrutura-Atividade
8.
Arch Pharm (Weinheim) ; 348(8): 541-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26085125

RESUMO

We here report an investigation of the interactions with tubulin of two types of molecules of a hybrid structural type consisting in a combretastatin A-4 moiety and a simplified pironetin fragment. The cytotoxicities of the molecules on two reference tumoral cell lines were measured. In addition, the effects of the compounds on the cell cycle and on microtubule assembly were observed. The dynamics of microtubule polymerization was investigated by means of immunofluorescence assays. It was thus established that at least some of the compounds under study exert their cytotoxic action by means of interaction with tubulin.


Assuntos
Desenho de Fármacos , Fragmentos de Peptídeos/metabolismo , Pironas/metabolismo , Estilbenos/metabolismo , Moduladores de Tubulina/metabolismo , Tubulina (Proteína)/metabolismo , Sítios de Ligação , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HT29 , Humanos , Concentração Inibidora 50 , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Polimerização , Ligação Proteica , Conformação Proteica , Pironas/química , Pironas/farmacologia , Estilbenos/química , Estilbenos/farmacologia , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Tubulina (Proteína)/efeitos dos fármacos , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
9.
Angew Chem Int Ed Engl ; 53(6): 1621-5, 2014 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-24470331

RESUMO

Laulimalide and peloruside A are microtubule-stabilizing agents (MSAs), the mechanism of action on microtubules of which is poorly defined. Here, using X-ray crystallography it is shown that laulimalide and peloruside A bind to a unique non-taxane site on ß-tubulin and use their respective macrolide core structures to interact with a second tubulin dimer across protofilaments. At the same time, they allosterically stabilize the taxane-site M-loop that establishes lateral tubulin contacts in microtubules. Structures of ternary complexes of tubulin with laulimalide/peloruside A and epothilone A are also solved, and a crosstalk between the laulimalide/peloruside and taxane sites via the M-loop of ß-tubulin is found. Together, the data define the mechanism of action of laulimalide and peloruside A on tubulin and microtubules. The data further provide a structural framework for understanding the synergy observed between two classes of MSAs in tubulin assembly and the inhibition of cancer cell growth.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Lactonas/química , Macrolídeos/química , Tubulina (Proteína)/metabolismo , Regulação Alostérica , Sítios de Ligação , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Cristalografia por Raios X , Dimerização , Humanos , Lactonas/metabolismo , Macrolídeos/metabolismo , Simulação de Dinâmica Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Tubulina (Proteína)/química
10.
Viruses ; 16(3)2024 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-38543715

RESUMO

African swine fever virus (ASFV) belongs to the family of Asfarviridae, part of the group of nucleocytoplasmic large DNA viruses (NCLDV). Little is known about the internalization of ASFV in the host cell and the fusion membrane events that take place at early stages of the infection. Poxviruses, also members of the NCLDV and represented by vaccinia virus (VACV), are large, enveloped, double-stranded DNA viruses. Poxviruses were considered unique in having an elaborate entry-fusion complex (EFC) composed of 11 highly conserved proteins integrated into the membrane of mature virions. Recent advances in methodological techniques have again revealed several connections between VACV EFC proteins. In this study, we explored the possibility of an analogous ASFV EFC by identifying ten candidate proteins exhibiting structural similarities with VACV EFC proteins. This could reveal key functions of these ASFV proteins, drawing attention to shared features between the two virus families, suggesting the potential existence of an ASFV entry-fusion complex.


Assuntos
Vírus da Febre Suína Africana , Febre Suína Africana , Poxviridae , Vacínia , Animais , Suínos , Vaccinia virus/genética , Vírus da Febre Suína Africana/genética , Vírus da Febre Suína Africana/metabolismo , Homologia de Sequência
11.
Ecancermedicalscience ; 17: 1580, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37533938

RESUMO

Background: Financial toxicity arises in cancer patients due to the objective financial burden of the disease or treatment, being associated with worse clinical outcomes. Direct non-medical spending on cancer patients undergoing radiotherapy in Peru under its publicly funded health system has not been described. Objective: To know the expenses related to the transfer of the radiotherapy outpatient. Methodology: For patients who started radiation therapy in 2021, treatment demographics and expenses related to transporting the patient from home to the radiation therapy center were prospectively collected. Association and connection tests were used, such as the Mann-Whitney/Kruskal-Wallis U-test and Spearman's Rho. A value of p < 0.05 is considered statistically significant. Results: 398 patients were collected, with average weekly expenses for transportation, lodging and food of $17.04, $6.69 and $45.91, respectively. Confirmation was positive between weekly spending and remoteness, likewise it was negative between effective teletherapy and remoteness, both analyses being statistically significant. Conclusion: The expense associated with transfer for radiotherapy is high, exceeding the average monthly income of the patient, as a consequence they have a worse therapeutic result, and may cause financial toxicity in cancer patients.

12.
Ecancermedicalscience ; 17: 1531, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37138970

RESUMO

Background and objectives: The standard treatment for locally advanced cervical cancer (CC) is chemoradiotherapy (CTRT) followed by high-dose-rate brachytherapy (HDRBT). The ideal scenario would be under novel intensity-modulated radiation therapy (IMRT) volumetric-modulated arc therapy (VMAT) radiation techniques over three-dimensional (3D) radiation therapy. However, radiotherapy (RT) centres in low- and middle-income countries have limited equipment for teletherapy services like HDRBT. This is why the 3D modality is still in use. The objective of this study was to analyse costs in a comparison of 3D versus IMRT versus VMAT based on clinical staging. Materials and methods: From 02/01/2022 to 05/01/2023 a prospective registry of the costs for oncological management was carried out for patients with locally advanced CC who received CTRT ± HDRBT. This included the administration of radiation with chemotherapy. The cost associated with patient and family transfers and hours in the hospital was also identified. These expenses were used to project the direct and indirect costs of 3D versus IMRT versus VMAT. Results: The treatment regimens for stage IIIC2, including 3D and novel techniques, are those with the highest costs. The administration of 3D RT for IIIC2 and novel IMRT or VMAT techniques, is $3,881.69, $3,374.76, and $2,862.80, respectively. The indirect cost from stage IIB to IIIC1 in descending order is IMRT, 3D and VMAT, but in IIIC2 the novel technique regimens reduce by up to 33.99% compared to 3D. Conclusion: In RT centres with an available supply of RT equipment, VMAT should be preferred over IMRT/3D since it reduces costs and toxicity. However, in RT centres where demand exceeds supply in the VMAT technique planning systems, the use of 3D teletherapy over IMRT/VMAT could continue to be used in patients with stage IIB to IIIC1.

13.
Biochemistry ; 51(1): 329-41, 2012 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-22148836

RESUMO

Cyclostreptin is the first microtubule-stabilizing agent whose mechanism of action was discovered to involve formation of a covalent bond with tubulin. Treatment of cells with cyclostreptin irreversibly stabilizes their microtubules because cyclostreptin forms a covalent bond to ß-tubulin at either the T220 or the N228 residue, located at the microtubule pore or luminal taxoid binding site, respectively. Because of its unique mechanism of action, cyclostreptin overcomes P-glycoprotein-mediated multidrug resistance in tumor cells. We used a series of reactive cyclostreptin analogues, 6-chloroacetyl-cyclostreptin, 8-chloroacetyl-cyclostreptin, and [(14)C-acetyl]-8-acetyl-cyclostreptin, to characterize the cellular target of the compound and to map the binding site. The three analogues were cytotoxic and stabilized microtubules in both sensitive and multidrug resistant tumor cells. In both types of cells, we identified ß-tubulin as the only or the predominantly labeled cellular protein, indicating that covalent binding to microtubules is sufficient to prevent drug efflux mediated by P-glycoprotein. 6-Chloroacetyl-cyclostreptin, 8-chloroacetyl-cyclostreptin, and 8-acetyl-cyclostreptin labeled both microtubules and unassembled tubulin at a single residue of the same tryptic peptide of ß-tubulin as was labeled by cyclostreptin (219-LTTPTYGDLNHLVSATMSGVTTCLR-243), but labeling with the analogues occurred at different positions of the peptide. 8-Acetyl-cyclostreptin reacted with either T220 or N228, as did the natural product, while 8-chloroacetyl-cyclostreptin formed a cross-link to C241. Finally, 6-chloroacetyl-cyclostreptin reacted with any of the three residues, thus labeling the pathway for cyclostreptin-like compounds, leading from the pore where these compounds enter the microtubule to the luminal binding pocket.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Paclitaxel/metabolismo , Mapeamento de Peptídeos , Compostos Policíclicos/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Sequência de Aminoácidos , Antibióticos Antineoplásicos/química , Antineoplásicos/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Dados de Sequência Molecular , Mapeamento de Peptídeos/métodos , Compostos Policíclicos/química , Moduladores de Tubulina/química
14.
Chemistry ; 18(10): 2875-89, 2012 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-22298309

RESUMO

The most common mode of bacterial resistance to aminoglycoside antibiotics is the enzyme-catalysed chemical modification of the drug. Over the last two decades, significant efforts in medicinal chemistry have been focused on the design of non- inactivable antibiotics. Unfortunately, this strategy has met with limited success on account of the remarkably wide substrate specificity of aminoglycoside-modifying enzymes. To understand the mechanisms behind substrate promiscuity, we have performed a comprehensive experimental and theoretical analysis of the molecular-recognition processes that lead to antibiotic inactivation by Staphylococcus aureus nucleotidyltransferase 4'(ANT(4')), a clinically relevant protein. According to our results, the ability of this enzyme to inactivate structurally diverse polycationic molecules relies on three specific features of the catalytic region. First, the dominant role of electrostatics in aminoglycoside recognition, in combination with the significant extension of the enzyme anionic regions, confers to the protein/antibiotic complex a highly dynamic character. The motion deduced for the bound antibiotic seem to be essential for the enzyme action and probably provide a mechanism to explore alternative drug inactivation modes. Second, the nucleotide recognition is exclusively mediated by the inorganic fragment. In fact, even inorganic triphosphate can be employed as a substrate. Third, ANT(4') seems to be equipped with a duplicated basic catalyst that is able to promote drug inactivation through different reactive geometries. This particular combination of features explains the enzyme versatility and renders the design of non-inactivable derivatives a challenging task.


Assuntos
Aminoglicosídeos/química , Antibacterianos/química , Canamicina/análogos & derivados , Canamicina/química , Nucleotidiltransferases/química , Nucleotidiltransferases/metabolismo , Aminoglicosídeos/farmacologia , Antibacterianos/farmacologia , Desenho de Fármacos , Canamicina/farmacologia , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Staphylococcus aureus/enzimologia , Staphylococcus aureus/genética
15.
Bioorg Med Chem Lett ; 22(24): 7693-6, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23103097

RESUMO

Colchicine was modified at the 10-OCH(3) position of the C-ring by reaction with heterocyclic amines or commercially available amines to afford a library of target colchicinoids in high yields (62-99%). Molecular modeling revealed that the incorporation of the linker groups led to a reduction in entropy and therefore binding affinity when compared with colchicine. Some colchicinoids were shown to be equicytotoxic with colchicine when evaluated in the DLD-1 colon cancer cells and retained activity in resistant A2780AD or HeLa cells with mutant Class III ß-tubulin. Importantly, unlike colchicine, the analogues in this study are amenable for prodrug derivatisation and with potential for tumor-selective delivery.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Colchicina/farmacologia , Pró-Fármacos/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/síntese química , Colchicina/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Modelos Moleculares , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade
16.
J Healthc Qual Res ; 37(3): 147-154, 2022.
Artigo em Espanhol | MEDLINE | ID: mdl-34887227

RESUMO

ANTECEDENT AND OBJECTIVE: In Peru, the presentation of TZM-IV and TZM-SC is carried out. But there is no comparative cost data by route of administration. The objective of our study was to know the costs of patients with breast cancer, comparing the routes of administration in a regional cancer center in Peru. MATERIAL AND METHODS: In 2020, patients who were prescribed TZM treatment were prospectively recorded clinical, demographic and transport data, and medical costs were obtained from medical history and pharmacy records. With these data, the simulation was performed in 100 patients who received 18 cycles of the drug. RESULTS: The main contributor to the cost of the difference was the cost of the drug itself, being S/. 4,711.11 (1,323.35 USD) and S/. 4,680.30 (1,314.69 USD) for TZM-IV and TZM-SC, respectively. The administration costs to treat 100 patients with complete cycles of TZM-IV and TZM-SC were S/. 334,488.53 (93,957.45 USD) and S/.207,455.33 (58,873.97 USD), respectively. Indirect costs indicate that patients lost in total, S/. 1,123.28 (315.53 USD) and S/. 1,148.60 (322.64 USD) in TZM-IV and TZMSC per patient, respectively. CONCLUSIONS: The use of TZM-SC is recommended, in the scenario of a lower cost of the drug and a shorter duration of administration time. Especially in a country with low funding, which only allows subsidizing the direct costs of cancer treatment.


Assuntos
Neoplasias da Mama , Administração Intravenosa , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Injeções Subcutâneas , Peru , Trastuzumab/efeitos adversos
17.
Ecancermedicalscience ; 16: 1406, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072238

RESUMO

Background and Objectives: Conventional long-course radiotherapy (LCRT) and a new paradigm of short-course radiotherapy with total neoadjuvant therapy (SCRT-TNT) are used in locally advanced rectal cancer (RC). There are few economic assessment reports available on TNT that focus on cost analysis in a country with limited funding for healthcare systems. The objective of this study was to perform a cost analysis comparing SCRT-TNT versus LCRT. Materials and Methods: In 2020-2021, a prospective registry was created to document RC patients who received neoadjuvant therapy and the costs of cancer treatments, transportation and the time patients and family members spent in the hospital. This registry outlined the direct and indirect costs of LCRT versus SCRT-TNT. Results: LCRT and SCRT-TNT regimens have direct costs that range from S/.5,993.30 to S/.27,928.36 and from S/.3,409.81 to S/.18,159.42, respectively. FOLFOX regimens are the most expensive. Administering radiotherapy in 28 3D sessions and 5 sessions of intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT) sessions costs S/.2,603.88, S/.1,277.19 and S/.1,027.77, respectively. The indirect cost of FOLFOX regimens is twice that of the similar modality that combines irradiation and Oxaliplatin IV and Capecitabine VO (CAPOX). SCRT-TNT regimens with CAPOX reduce costs by at least 50%, while SCRT-TNT regimens with FOLFOX reduce costs by 32%. Conclusion: Despite using IMRT/VMAT, SCRT-TNT is a less expensive approach for patients with RC when compared to LCRT. The costs to patients using SCRT-TNT are much lower, but it is also a better option because it saves hospital resources.

18.
Bioengineering (Basel) ; 9(12)2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36550969

RESUMO

(1) Background: Cervical spinal cord injury (SCI) patients have impairment in the autonomic nervous system, reflected in the cardiovascular adaption level during the performance of upper limb (UL) activities carried out in the rehabilitation process. This adaption level could be measured from the heart rate (HR) by means of wearable technologies. Therefore, the objective was to analyze the feasibility of using Xiaomi Mi Band 5 wristband (XMB5) for HR monitoring in these patients during the performance of UL activities; (2) Methods: The HR measurements obtained from XMB5 were compared to those obtained by the professional medical equipment Nonin LifeSense II capnograph and pulse oximeter (NLII) in static and dynamic conditions. Then, four healthy people and four cervical SCI patients performed a UL training based on six experimental sessions; (3) Results: the correlation between the HR measurements from XMB5 and NLII devices was strong and positive in healthy people (r = 0.921 and r = 0.941 (p < 0.01) in the static and dynamic conditions, respectively). Then, XMB5 was used within the experimental sessions, and the HR oscillation range measured was significantly higher in healthy individuals than in patients; (4) Conclusions: The XMB5 seems to be feasible for measuring the HR in this biomedical application in SCI patients.

19.
Biophys J ; 101(12): 2970-80, 2011 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-22208196

RESUMO

Microtubules assembled with paclitaxel and docetaxel differ in their numbers of protofilaments, reflecting modification of the lateral association between αß-tubulin molecules in the microtubule wall. These modifications of microtubule structure, through a not-yet-characterized mechanism, are most likely related to the changes in tubulin-tubulin interactions responsible for microtubule stabilization by these antitumor compounds. We have used a set of modified taxanes to study the structural mechanism of microtubule stabilization by these ligands. Using small-angle x-ray scattering, we have determined how modifications in the shape and size of the taxane substituents result in changes in the interprotofilament angles and in their number. The observed effects have been explained using NMR-aided docking and molecular dynamic simulations of taxane binding at the microtubule pore and luminal sites. Modeling results indicate that modification of the size of substituents at positions C7 and C10 of the taxane core influence the conformation of three key elements in microtubule lateral interactions (the M-loop, the S3 ß-strand, and the H3 helix) that modulate the contacts between adjacent protofilaments. In addition, modifications of the substituents at position C2 slightly rearrange the ligand in the binding site, modifying the interaction of the C7 substituent with the M-loop.


Assuntos
Microtúbulos/química , Microtúbulos/ultraestrutura , Modelos Químicos , Modelos Moleculares , Taxoides/química , Sítios de Ligação , Simulação por Computador , Ligação Proteica , Relação Estrutura-Atividade , Difração de Raios X
20.
Biology (Basel) ; 10(11)2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34827203

RESUMO

BACKGROUND: Rhythmic gymnastics performance is characterized by technical elements involving flexibility, aerobic capacity and strength. Increased core strength in rhythmic gymnastics could lead to improved sporting performance. OBJECTIVE: The aim of this study was to analyze the effect of 12 weeks of core muscle training on core muscle performance in rhythmic gymnasts. METHODS: A randomized controlled study involving 24 rhythmic gymnastics was conducted. Participants were randomly assigned to a control group (CG; n = 12; age 13.50 ± 3.17 years) or a training group (TG; n = 12; age 14.41 ± 2.35 years). Body composition, isometric strength of trunk, core endurance and core muscle electromyographic activity were measured (EMG) after 12 weeks of core training. Independent sample t-tests were carried out to compare baseline values between groups. A two-way repeated-measures analysis of variance (ANOVA) (time × group) was applied. RESULTS: The TG improved body composition, trunk lean mass (mean differences MD = -0.31; p = 0.040), lean mass (MD = 0.43; p = 0.037) and bone mass (MD = -0.06; p < 0.001) after training. Core training increased isometric strength of trunk, flexion test (MD = -21.53; p = 0.019) and extension test (MD = 22.7; p = 0.049), as well as the prone bridge core endurance test (MD = -11.27; p = 0.040). The EMG values also increased in the TG in prone bridge for front trunk (MD = -58.58; p = 0.026). CONCLUSIONS: Core strength training leads to improvements in body composition, as well as improvements in trunk strength and increases in muscle electromyographic activity. These improvements could therefore improve performance during competitive rhythmic gymnastics exercises.

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